Sterol efflux is an atheroprotective function attributed to HDL. We have identified plasminogen as a mediator of sterol efflux through ABCA1 transporter. Lipoprotein(a), an independent risk factor for cardiovascular disease inhibits plasminogen’s ability to sterol efflux. Patients with high Plasma Lp(a) levels have reduced sterol efflux capacity. Our goal is to identify how plasminogen-Lp(a)-ABCA1 axis contributes to cardiovascular disease.
PCSK9 is a circulating protein that blocks LDL receptors in the liver and prevents LDL clearance. Because the response to PCSK9 blocking antibodies is not uniform (from none to 70% effective) in patients, we take advantage of the patient registry and biorepository and mouse models to understand PCSK9 metabolism. A subcohort of our patients in the registry is part of a clinical trial for PCSK9 inhibition therapy. We are proposing to understand how PCSK9 is regulated and how it binds other lipoproteins such as Lipoprotein(a), with the goal of developing novel diagnostic tests and identify additional therapeutic targets to inhibit the effect of PSCK9.
We believe metrics other than HDL cholesterol levels are better predictors of disease risk. We have previously shown in mice that HDL proteome is hereditary. To identify what specific HDL protein signatures associate with CVD or stroke, we investigate HDL function and proteome in human cardiovascular disease and stroke through proteomics and genetics. Reasons for Geographic and Racial Differences in Stroke (REGARDS) longitudinal cohort is used to identify the sex and race dependent interactions between novel HDL metrics and cardiovascular disease and stroke.
Increased epicardial adipose tissue volume is an independent risk for heart failure. We work to identify the relationship between epicardial adipose tissue and heart failure by deep phenotyping. Although both visceral adipose depots, in macaques mesenteric and epicardial adipose tissues are distinct by their proteomes, secretomes, vascular density and call size. Epicardial adipose tissue favors increased mitochondrial turnover with enhanced fatty acid oxidation.